Castellaneta has done some live-action acting on shows such as ALF, Stargate SG-1, and a couple of episodes of Fox's Married with Children. He appeared in Matt Groening's sister production Futurama as the Robot Devil. Castellaneta also appeared in the James L. Brooks 1989 film War of the Roses as a man seeking a divorce, marking the first time Brooks and Castellaneta worked on a Gracie Films production aside from The Simpsons.
As well as that, he was in the Matt Groening film, Olive The Other Reindeer and he is in the crowd of a basketball game in Space Jam.

A native of Chicago, Castellaneta graduated from Oak Park and River Forest High School and Northern Illinois University. After college, Dan went on to work at Chicago's Second City, which he later recalled on Inside the Actors Studio as "a place that, if you're not funny going in, will train you on how to be funny when going out."

He is married to writer Deb Lacusta. In an interview, Dan says he never talks about the Simpsons at home, but has admitted on a couple of occasions that if his wife is making lunch he may (like Homer) remark, "Mmm, sandwiches!"

Castellaneta has a knack for music. He has composed and/or written three songs for The Simpsons, "They'll Never Stop The Simpsons," "Dancing Workers Song," and "The Gay Song". He also released two albums, Two Lips and I Am Not Homer. The former is an all-music album while the latter is an all-comedy album and contains the song "So Dumb (Homer's Lament)", which Castellaneta wrote and sang as Homer, Grampa, Groundskeeper Willie and Barney. Castellaneta also did all the singing when Homer had become an opera singer, which is uncommon as professional singers will often "step in" to sing for animated characters. Guest Plácido Domingo had commented that Castellaneta's opera singing had been remarkable.